: The v-Rel oncoprotein of the highly oncogenic retrovirus reticuloendotheliosis virus strain T (Rev-T) induces aggressive and fatal leukemia/lymphoma in chickens and transgenic mice. Its cellular homolog c-Rel is essential for lymphoid cell survival and proliferation, and for immune and inflammatory responses. Both v-Rel and c-Rel belong to the Rel/NF-KB family of transcription factors. Members of this family share extensive sequence similarity in their N-terminal Rel-homology domain, activate the transcription of genes linked to kB DNA sites and exhibit related biological activities. Chromosomal amplification, rearrangement, overexpression and/or constitutive activation of rel/nf-kb genes are implicated in many human hematopoietic tumors such as lymphoma, leukemia, myeloma and Hodgkin's disease. Aberrant rel/nf-kb genes and activity are also observed in solid tumors such as lung, breast, colon, ovarian and prostate carcinomas. It is therefore important to elucidate how the ReI/NF-kB proteins function in oncogenesis and to understand their regulation. While most vertebrate cellular ReI/NF-kB factors have been implicated in human cancer, none of them is acutely oncogenic when expressed in primary cells or in transgenic mice. The retroviral oncoprotein v-Rel therefore provides an excellent and unique tool tO directly address the function and regulation of these factors in the physiologically relevant context of primary lymphoid cells. Our studies of the past few years support the notion that lymphoid cell transformation by v-Rel results from the activation of specific cellular genes, and point to its regulation by phosphorylation. Our analyses also demonstrated an absolute correlation between the anti-apoptotic and oncogenic activities of v-Rel transactivation mutants. This application for continuation of support will investigate how v-Rel-mediated transactivation effects cell survival, proliferation and oncogenesis (Aim. 1). Experiments are also proposed to further characterize the transactivation function of v-Rel and c-Rel and its mode of action (Aim. 2), and to explore the role of phosphorylation in its regulation (Aim. 3). Collectively, these studies will clarify the pathways through which the viral oncoprotein v-Rel functions in malignant lymphoid cell transformation. This work will also provide invaluable insights into the events necessary for the oncogenic conversion of cellular ReI/NF-KB factors.